Method of producing a diuretic effect with p-carboxybenzenesulfonamide



United States Patent METHOD OF PRODUCING A DIURETIC EFFECT WITHp-CARBOXYBENZENESULFONAMIDE No Drawing. Application November 24, 1952,

Serial No. 322,356

5 Claims. (Cl. 167-55) This invention relates to diuretic compositions,and more particularly to a composition containing an agent which servesto increase the elimination of cations, principally sodium andpotassium.

The invention also involves the process of increasing the elimination ofcations, and more particularly the sodium cation, from the body of manor other animals. This process involves the administration of the activeagent and the regulation of the quantity consumed so as to bring aboutthis desired result.

Many persons suffer from an abnormal retention of sodium, principally asthe chloride. This may result in the development of edema, mayprecipitate an episode of congestive heart failure, or may aggravate apre-existing hypertension. One way to overcome this is to decrease theamount of sodium chloride intake, but-this is an unsatisfactory solutionfor the reason that many such foods are unpalatable. That is, peopleobject so much to the bland taste of the food that they refuse to adhereto a regime of an extremely low salt consumption.

In accordance with the present invention a composition is providedwhich, when consumed, makes it possible for a person to apply thedesired amounts of salt to his food. The composition of the inventionserves to provide for excretion of a major amount of this salt intakewith the result that the patient is allowed a diet to which he willadhere and at the same time the daily salt balance approximates thatresulting from moderate to severe salt restriction without the aid ofthis invention.

Furthermore, there are a number of clinical indications for the use ofthe composition of the invention. In various edematous states it isdesirable to eliminate cations, and principally the sodium cations, fromthe body, in order to bring about a reduction of the edematouscondition. By giving such a patient the composition of the invention,this condition will be markedly improved.

The value of salt restriction as a means of limiting the development ofedema is well documented. The composition of the invention may beparticularly useful in the patient prone to congestive heart failure.

The active agent of the composition of the invention ispara-carboxybenzenesulfonamide (or 'para-sulfamylbenzoic acid), havingthe structural formula:

no 0 o-Q-s ORNH! This active agent may be combined with either a solidor a liquid carrier or diluent. The resulting compound may be put up inthe form of tablets, powder, or capsules, or in any form which can beused for oral consumption. Likewise, the liquid preparation may bebottled or even put up in encapsulated form for ease of oraladministration. The liquid form may as well be for parenteraladministration and in this event precautions should of course be takento produce a sterile composition. I

In making the composition, conventional pharmaceutical practices may becarried out andthis applies to com- 2,789,938 Patented Apr. 23, 1957positions for either oral or parenteral use. Ordinary care should beexercised to make sure that no incompatible condition exists withrespect to the diluent which is being employed. In the liquidpreparation, the active ingredient may be either in complete solution ormay be in suspension.

Irrespective of the particular kind of dosage form which is made, theunit dosage of the composition should contain therapeutic amounts of theactive agent. Thus, a unit dosage of the ingredient will contain from 10mg. to 16 gm., a more preferred range being from 100 mg. to 4.0 gm. Thetotal daily oral intake for an adult should be from 0.5 to 16 grams, andmost generally from 2 to 8 grams. About one-fourth these amounts wouldbe taken parenterally. Bearing in mind that a person required to takethis composition will ordinarily prefer at one time to take one or a fewtablets or capsules, or one or a few tablespoons of a liquidpreparation, or a few cc. of an injectable preparation, the frequency ofadministration is apparent.

As a further feature of the invention, compositions are provided whichare free of any material amounts of sodium or potassium. As a primarypurpose of the invention is to increase the elimination of thesecations, it follows that it would be desirable not to introduce anysodium or potassium into the person with the active agent of theinvention. As ordinary pharmaceutical compositions contain sodium andpotassium compounds, a feature of the invention resides in theirelimination (other than as slight contaminants) from the compositions ofthe invention.

Representative compositions, in accordance with the invention, are thefollowing, and from them other suitable compositions will be apparent.

Example I.Compressea' tablets p-Carboxybenzenesulfonamide 57 lb. 13 oz.Dextrine white NF V 4 lb. 8 oz. Corn starch paste, 1 part Gelatinsolution, 2 parts "i 1 8 Distilled water, q. s.

Starch USP dried-MP 3000 7 lb. 8 oz. Talc USP 3 1b. 8 oz. Magnesiumstearate purif. imp. powd 3 oz.

Total weight granulation lb.

Compress into 0.65 gram tablets each containing 0.5 gram ofp-carboxybenzenesulfonamide. Theoretical yield: 52,500.

Example lI.Sterile solution Grams Ammomia water 28.3% NH; 19.54p-Carboxybenzenesulfonamide 50 Pyrogen-free double distilled Water, q.s.

Example III.-Dry filled capsules Kg. p-Carboxybenzenesulfonamide 4 Cornstarch USP 0.8

" Yield: 8000 capsules each containing 0.5 gram ofpcarboxybenzenesulfonamide.

Example I V.Sft elastic capsules p-Carboxybenzenesulfonamide "kilo-..Peanut oil, q. s. (to form soft creamy mixture).

Make into soft elastic capsules of a suitable size, each capsulerepresenting 500 mg. p-carboxybenzenesulfonamide.

Example V.-Saspension (oral) Distilled Water, q. s. ad.

Each cc. of the suspension mixture contains 1.0 gram of thep-carboxybenzenesulfonamide.

Example V I .Effervescent granule p-Carboxybenzenesulfonamide kg 4Dulcin kg 0.025

Calcium carbonate powder USP kg 3.375

Corn starch paste 12.5% 1000 cc. allow kg 0.100

Distilled water, a sufficient quantity about 250 cc.

Citric acid fine USP granules kg 0.5 8.0

Yield: 2000 doses. Each 4 gm. of granular material contains 2 gm. ofpcarboxybenzenesulfonamide.

Example VII .Granale p-Carboxybenzenesulfonamide kg 4 Powdered sugar USPkg 1.5 Corn starch USP kg 0.5

Distilled water, a suflicient quantity, about 1000 cc.

6 Yield: 2000 doses. Each 3 gm. dose of granular material contains 2 gm.of p-carboxybenzenesulfonamide.

Example VIII .Efiervescent tablet p-Carboxybenzenesulfonamide kg. 4Dulcin kg 0.025 Calcium Carbonate USP powder kg 3.325

Corn starch paste 12.5% 1.5 liters allow kg 0.150

Distilled water, a suflicient quantity, about 0.5 liter.

Citric acid USP fine granules kg 0.47

Magnesium stearate .kg 0.03

Theoretical yield: 2000 tablets, each weighing 4 grams and eachcontaining 2 grams of p-carboxybenzenesulfonamide.

Example IX.Efiervescent powder Kg. p-Carboxybenzenesulfonamide 4 Dulcin0.025 Calcium carbonate USP powder 3.475 Citric acid USP powder 0.5 8.0

Yield: 2000 doses of 4 grams each, each containing 2 grams ofp-carboxybenzenesulfonamide.

Example X .Powder p-Carboxybenzenesulfonamide 4 Powdered sugar USP 2Yield: 2000 doses, each weighing 3 grams and each containing 2 grams ofp-carboxybenzeuesulfonamide.

Other examples of the composition of the invention having thep-carboxybenzenesulfonamide present in smaller or greater concentrationwill be apparent. Thus the active agent could be present in as low as 1or 2% by weight of the composition, especially if a clear aqueoussolution of relatively insoluble derivatives (hereinafter mentioned) ofthe p-carb0xybenzenesulfonamide are to be used. However, because of therelatively large amount of the active agent which must be taken daily,the higher relative proportions, as 10% and more, are to be recommendedand this may be even if the patient can tolerate the undilutedp-carboxybenzenesulfonamide. The active material in this latter case canbe packaged as the pure compound and be labeled for medicinal use withinstructions by the physician as to the quantity and frequency ofconsumption by the patient.

As has been mentioned, a daily amount of from 2 to 16 grams may beprescribed. In most instances the daily intake will be from 4 to 8grams. The attending physician can determine the proper dailyconsumption by physical observation of the patient and by measurement ofthe patients sodium and potassium balance. Based on this information,the daily administration should be regulated to approximately theminimum to bring about and maintain the desired sodium and potassiumelimination.

Although the invention has been described with particular reference top-carboxybenzenesulfonamide, numerous derivatives of it may be employedas they presumably yield this acid in the body. For example, as isevident from Example II, the ammonium salt may be utilized. The sodiumor potassium salt may be used, but as has been mentioned, this iscounterindicated as it introduces the ions which are intended to beeliminated from the body. Other salts may be utilized by replacing thehydrogen of the carboxyl group.

The invention contemplates as well other derivatives of the acid, andthis includes the lower alkyl esters, the amide, and either the mono orthe disubstituted lower alkyl derivatives of the amide form.Representative compounds which may be substituted in the above examplesin amounts to yield an equivalent therapeutic effeet, are the following:

Ethyl p-sulfamylbenzoate p-Sulfamy1benzamide CHaNHOC SOzNHzp-Sulfamyl-N-methylbenzamlde (CHa)2NOC SOgNHs p-Sulfamyl-N,Ndlmethylbenzamide 3 1) 2 O C S OzNHz p-Sulfamyl-N,N-di-n-propylbenzamideIll-04119020 SOzNHQ n-Butyl p-sultamylbenzoate OHOzC Cs sec-Butylp-sulfamylbenzoate S OgNHt .7 a ll Cyclohexyl p-sulfamylbenzoatetert.-Buty1 p-sulfamylbenzoate 2-diethylaminoethyl p-sulfamylbenzoatehydrochloride 2-diethy1aminoethyl p-sulfamylbenzamide hydrochlorideNHzNHO C SOzN H2 p-Sulfamylbenzoyl hydrazine SO.NH.

m-Carboxybenzenesulfonamide S OzNH:

o-Carboxybenzenesulfonamide NHzNH O C I @s 021N112 m-Sulfamylbenzoylhydrazine S OzN H2 O-Sulfumylbenzoyl hydrazine o-Chloro--sulfamylbenzoie acid CHsO p-Sulfamyl-o-methoxybenzoic acid sium ionsfrom the body which consists in administering to a living personsuffering from an abnormal retention of these ionsp-carboxybenzenesulfonamide in an amount suflicient to eliminate theexcess sodium and potassium ions and bring about the desired electrolytebalance in the person.

2. The process of increasing the elimination of an ion selected from thegroup consisting of sodium and potassium ions from the body whichconsists in orally administering to a living person suffering from anabnormal retention of these ions p-carboxybenzenesulfonamide in anamount sufiicient to eliminate the excess sodium and potassium ions andbring about the desired electrolytic balance in the person.

3. The process of increasing the elimination of an ion selected from thegroup consisting of sodium and potassium ions from the body whichconsists in parenterally administering to a living person suifering froman abnormal retention of these ions p-carboxybenzenesulfonamide in anamount sufficient to eliminate the excess sodium and potassium ions andbring about the desired electrolyte balance in the person.

4. The process of increasing the elimination of an ion selected from thegroup consisting of sodium and potassium ions from the body whichconsists in administering to a living person suffering from an abnormalretention of these ions from A; to 16 grams daily ofp-carboxybenzenesulfonamide in an amount suflicient to eliminate theexcess sodium and potassium ions and bring about the desired electrolytebalance in the person.

5. A method of increasing the elimination of an ion selected from thegroup consisting of sodium and potassium ions from the body Whichcomprises administering a composition comprising not less than 1.0% byweight of p-carboxybenzenesulfonarnide to a person suffering from anabnormal retention of these ions.

References Cited in the file of this patent UNITED STATES PATENTS MillerAug. 26, 1952 Fiechtinger Dec. 29, 1953 OTHER REFERENCES

1. THE PROCESS OF INCREASING THE ELIMINATION OF AN ION SELECTED FROM THEGROUP CONSISTING OF SODIUM AND POTASSIUM IONS FROM THE BODY WHICHCONSISTS IN ADMINISTERING TO A LIVING PERSON SUFFERING FROM AN ABNORMALRETENTION OF THESE IONS P-CARBOXYBENZENESULFONAMIDE IN AN AMOUNTSUFFICIENT TO ELIMINATE THE EXCESS SODIUM AND POTASSIUM IONS AND BRINGABOUT THE DESIRED ELECTROLYTE BALANCE IN THE PERSON.